Tumorigenesis is associated with the disbalance of oncogenes and antioncogenes. For almost all of the oncogenes or antioncogenes, their functions and effects are finally converged to cell cycle. Therefore, tumor can be taken as a cell cycle disease (CCD), and it is one of the routes for treating tumor by regulating or blocking cell cycle. In current, it is found that there are a lot of molecules associated with cell cycle regulation, among which Cyclin-Dependent-Kinases (CDKs) are core molecules of cell cycle regulatory network. CDKs, as catalytic subunits, are a class of Ser/Thr kinases, which participate in different stages of cell cycle as important signaling molecules in cells. Studies show that in a cell cycle regulatory network with CDKs as core, any abnormity would result in abnormal cell cycle and finally result in tumorigenesis. CDK family now has 21 isoforms, which work by binding to their regulatory subunit cyclins. In addition to the role in regulating the cell cycle, CDK isoforms are also involved in regulating transcription, DNA repair, differentiation and programmed cell death. Based on the key role of CDKs in regulating proliferation and death of tumor cells, the family of CDKs provides a chance and a new field for the discovery and development of anti-tumor drugs.
In the development of drugs, the first generation of CDK inhibitors, represented by flavopiridol, UCN-01 and the like, are designated as “pan-CDK” inhibitors, which block all the isoforms of CDK family equivalently and exhibit a relatively high toxicity in clinical trial, and some of them cannot be administered in a therapeutically effective amount. Therefore, human begins to develop selective CDK inhibitors to enhance the selectivity of the therapy and prevent normal cells from injury by some side effects.
Among the CDK isoforms involved in cell cycle, CDK4/6 plays an unreplaceable role. Cancer-associated cell cycle mutations are mainly present in G1 phase and G1/S transition. The complex formed by CDK4/6 and Cyclin D releases the bound transcriptional factor E2F by phosphorylation (pRb) of the antioncogene product Rb, and triggers transcription of genes associated with S phase, thereby promoting cells to pass the checkpoint and to transit from G1 phase to S phase. About 80% of human tumors are abnormal in cyclin D-CDK4/6-INK4-Rb pathway. Due to the alteration of the pathway, the G1 phase is accelerated so that tumor cells have the proliferation sped up and thus acquire survival advantage. Therefore, the interference of the pathway has become a strategy of treatment, and CDK4/6 has become a new anti-tumor target. CDK4/6 as anti-tumor target has the following advantages: (1) for most of proliferative cells, their proliferation is CDK2 or CDK4/6-dependent, however, CDK4/6 inhibitors do not exhibit the cytotoxicity of “pan-CDK inhibitors”, such as bone marrow depression and intestinal reaction; and (2) preclinical tests show that if cyclin D level is increased or P16INK4a is inactivated in cells, the sensitivity of cells to drugs can be increased; since tumor cells have said phenomena relative to normal cells, the targeting property of drugs is increased to some extent.
So far, no CDK inhibitor drugs are approved for commercial marketing. A series of CDK4/6 inhibitors with good selectivity, which have been reported by some pharmaceutical companies including Pfizer, Eli Lilly and Novartis, are in clinical trials. Among them, of particular concern are PD0332991 (palbociclib) developed by Pfizer, LY2835219 (Phase III) developed by Eli Lilly and LEE-011 (Phase III) developed by Novartis

In April, 2013, Pfizer's PD0332991 received Breakthrough Therapy Designation from Food And Drug Administration (FDA); and in August, 2014, Pfizer submitted with FDA a New Drug Application (NDA) intended for approval of PD0332991 (palbociclib) in combination with letrozole as treatment of post-menopausal women with locally advanced or metastatic breast cancer, who are estrogen receptor-positive (ER+) and human epidermal growth factor 2 negative (HER2−), and did not received systemic treatment previously. It has very positive effect on the development of CDK4/6 inhibitors.
In order to achieve a better therapeutic effect for tumor and to better meet the market demand, the inventors hope to develop a new generation of CDK4/6 inhibitors with high efficacy and low toxicity. The invention provides selective CDK4/6 inhibitors with a new structure, and finds that the compounds with such a structure have good efficacy, and can effectively pass through the blood brain barrier, which makes CDK inhibitors as therapy for brain cancer possible.